tbuckley/cabot-search huggingface dataset:
Cefiderocol resistance genomics in sequential chronic Pseudomonas aeruginosa isolates from cystic fibrosis patients
Authors: Carla López-Causapé, Ainhize Maruri-Aransolo, María A. Gomis-Font, Iván Penev, María García Castillo, Xavier Mulet, Juan de Dios Caballero, Rosa del Campo, Rafael Cantón, Antonio Oliver
Journal: Clinical Microbiology and Infection (2022)
Retrospective review of pediatric patch testing results in skin of color
Authors: Katherine Young, Reid W. Collis, David Sheinbein, Chelsea Shope, Tara Suresh, Idy Tam, Alan Snyder, Colleen Cotton, Raegan Hunt, Alina Goldenberg, Ari Goldminz, Aida Lugo-Somolinos, Eric Grisham, Kari L. Martin, Mandeep Sandhu, Dawn Eichenfield, Jessica Sprague, Elana Kleinman, Katie Sum, Jennifer K. Chen, Joyce Teng, Marcella R. Aquino, John Plante, Katlein Franca, Alejandra Onate, Patricia Udrizar, Walter Liszewski, JiaDe Yu
Journal: Journal of the American Academy of Dermatology (2022)
Neutralization of Omicron Subvariant BA.2.75 after Bivalent Vaccination
Authors: Spyros Chalkias, Jing Feng, Xing Chen, Honghong Zhou, Jean-Claude Marshall, Bethany Girard, Joanne E Tomassini, Barbara J Kuter, David C Montefiori, Rituparna Das
Journal: New England Journal of Medicine (2022)
Reproductive Health Care Is a Key Component of Comprehensive Care for Adolescents with CKD
Authors: Monica L. Reynolds, Andrea L. Oliverio, Celina Brunson, Marva Moxey-Mims
Journal: Journal of the American Society of Nephrology (2022)

Reynolds, Monica L.; Oliverio, Andrea L.; Brunson, Celina; Moxey-Mims, Marva Author Information
Long-term multidrug- and rifampicin-resistant tuberculosis treatment outcome by new WHO definitions in Germany
Authors: Ralf Otto-Knapp, Brit Häcker, David Krieger, Katarina Stete, Katharina Starzacher, Christina Maier, Jan Heyckendorf, Korkut Avsar, Isabelle Suárez, Jan Rybniker, Torsten Bauer, Gunar Günther, Christoph Lange
Journal: European Respiratory Journal (2022)

<b>Long-term outcomes of MDR/RR-TB with 3-year follow-up show 62% favourable outcomes in Germany. 26% were lost to follow-up or transferred. It was possible to categorise 95% of favourable outcomes as cured using the 2021 WHO outcome definitions.</b> https://bit.ly/3bJnvfR
Multi-site cross-organ calibrated deep learning (MuSClD): Automated diagnosis of non-melanoma skin cancer
Authors: Yufei Zhou, Can Koyuncu, Cheng Lu, Rainer Grobholz, Ian Katz, Anant Madabhushi, Andrew Janowczyk
Journal: Medical Image Analysis (2022)

Although deep learning (DL) has demonstrated impressive diagnostic performance for a variety of computational pathology tasks, this performance often markedly deteriorates on whole slide images (WSI) generated at external test sites. This phenomenon is due in part to domain shift, wherein differences in test-site pre-analytical variables (e.g., slide scanner, staining procedure) result in WSI with notably different visual presentations compared to training data. To ameliorate pre-analytic variances, approaches such as CycleGAN can be used to calibrate visual properties of images between sites, with the intent of improving DL classifier generalizability. In this work, we present a new approach termed Multi-Site Cross-Organ Calibration based Deep Learning (MuSClD) that employs WSIs of an off-target organ for calibration created at the same site as the on-target organ, based off the assumption that cross-organ slides are subjected to a common set of pre-analytical sources of variance. We demonstrate that by using an off-target organ from the test site to calibrate training data, the domain shift between training and testing data can be mitigated. Importantly, this strategy uniquely guards against potential data leakage introduced during calibration, wherein information only available in the testing data is imparted on the training data. We evaluate MuSClD in the context of the automated diagnosis of non-melanoma skin cancer (NMSC). Specifically, we evaluated MuSClD for identifying and distinguishing (a) basal cell carcinoma (BCC), (b) in-situ squamous cell carcinomas (SCC-In Situ), and (c) invasive squamous cell carcinomas (SCC-Invasive), using an Australian (training, n = 85) and a Swiss (held-out testing, n = 352) cohort. Our experiments reveal that MuSCID reduces the Wasserstein distances between sites in terms of color, contrast, and brightness metrics, without imparting noticeable artifacts to training data. The NMSC-subtyping performance is statistically improved as a result of MuSCID in terms of one-vs. rest AUC: BCC (0.92 vs 0.87, p = 0.01), SCC-In Situ (0.87 vs 0.73, p = 0.15) and SCC-Invasive (0.92 vs 0.82, p = 1e-5). Compared to baseline NMSC-subtyping with no calibration, the internal validation results of MuSClD (BCC (0.98), SCC-In Situ (0.92), and SCC-Invasive (0.97)) suggest that while domain shift indeed degrades classification performance, our on-target calibration using off-target tissue can safely compensate for pre-analytical variabilities, while improving the robustness of the model.
Whole-exome sequencing identifies novel protein-altering variants associated with serum apolipoprotein and lipid concentrations
Authors: Niina Sandholm, Ronja Hotakainen, Jani K. Haukka, Fanny Jansson Sigfrids, Emma H. Dahlström, Anni A. Antikainen, Erkka Valo, Anna Syreeni, Elina Kilpeläinen, Anastasia Kytölä, Aarno Palotie, Valma Harjutsalo, Carol Forsblom, Per-Henrik Groop
Journal: Genome Medicine (2022)

Abstract Background Dyslipidemia is a major risk factor for cardiovascular disease, and diabetes impacts the lipid metabolism through multiple pathways. In addition to the standard lipid measurements, apolipoprotein concentrations provide added awareness of the burden of circulating lipoproteins. While common genetic variants modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesterolemia and other genetic disorders of lipid metabolism. We aimed to identify low-frequency protein-altering variants (PAVs) affecting lipoprotein and lipid traits. Methods We analyzed whole-exome (WES) and whole-genome sequencing (WGS) data of 481 and 474 individuals with type 1 diabetes, respectively. The phenotypic data consisted of 79 serum lipid and apolipoprotein phenotypes obtained with clinical laboratory measurements and nuclear magnetic resonance spectroscopy. Results The single-variant analysis identified an association between the LIPC p.Thr405Met (rs113298164) and serum apolipoprotein A1 concentrations ( p =7.8×10 −8 ). The burden of PAVs was significantly associated with lipid phenotypes in LIPC , RBM47 , TRMT5 , GTF3C5 , MARCHF10 , and RYR3 ( p &lt;2.9×10 −6 ). The RBM47 gene is required for apolipoprotein B post-translational modifications, and in our data, the association between RBM47 and apolipoprotein C-III concentrations was due to a rare 21 base pair p.Ala496-Ala502 deletion; in replication, the burden of rare deleterious variants in RBM47 was associated with lower triglyceride concentrations in WES of &gt;170,000 individuals from multiple ancestries ( p =0.0013). Two PAVs in GTF3C5 were highly enriched in the Finnish population and associated with cardiovascular phenotypes in the general population. In the previously known APOB gene, we identified novel associations at two protein-truncating variants resulting in lower serum non-HDL cholesterol ( p =4.8×10 −4 ), apolipoprotein B ( p =5.6×10 −4 ), and LDL cholesterol ( p =9.5×10 −4 ) concentrations. Conclusions We identified lipid and apolipoprotein-associated variants in the previously known LIPC and APOB genes, as well as PAVs in GTF3C5 associated with LDLC, and in RBM47 associated with apolipoprotein C-III concentrations, implicated as an independent CVD risk factor. Identification of rare loss-of-function variants has previously revealed genes that can be targeted to prevent CVD, such as the LDL cholesterol-lowering loss-of-function variants in the PCSK9 gene. Thus, this study suggests novel putative therapeutic targets for the prevention of CVD.
Focused Cardiac Ultrasonography for Right Ventricular Size and Systolic Function
Authors: Gabriel Prada, Aliaksei Pustavoitau, Seth Koenig, Carol Mitchell, Raymond F. Stainback, José L. Díaz-Gómez
Journal: New England Journal of Medicine (2022)

This video presents a practical method for conducting visual, semiquantitative assessment of right ventricular size and systolic function with focused cardiac ultrasonography.
Rectal organoid-guided CFTR modulator therapy restores lung function in a cystic fibrosis patient with the rare 1677delTA/R334W genotype
Authors: Georgia Mitropoulou, Nathalie Brandenberg, Sylke Hoehnel, Camilla Ceroni, Zisis Balmpouzis, Sylvain Blanchon, Gian Dorta, Alain Sauty, Angela Koutsokera
Journal: European Respiratory Journal (2022)

<b><i>Ex vivo</i> analysis of intestinal organoids has great translational potential as a precision medicine tool for the prediction of clinical efficacy of CFTR modulators and, for patients with rare variants, may hold the key to these life-changing therapies</b> http://bit.ly/3G1FkDp
Mucosal IgA against SARS-CoV-2 Omicron Infection
Authors: Mikael Åberg, Anna Smed-Sörensen, Charlotte Thålin
Journal: New England Journal of Medicine (2022)

Mucosal IgA against SARS-CoV-2 Omicron InfectionTo the Editor: Havervall et al. (Oct.6 issue) 1 suggest that wild-type SARS-CoV-2 spike-specific mucosal IgA may provide protection against omicron (B.1.1.529)breakthrough infection.We detected salivary anti-receptor-binding domain (RBD) IgA antibodies against G614 RBD in 48 of 67 vaccinated healthy persons (72%) at 5 to 59 days after receiving a dose of messenger RNA (mRNA) vaccine -in 12 of 18 (67%) after dose 1, in 22 of 34 (65%) after dose 2, and in 14 of 15 (93%) after dose 3. We also observed these antibodies in 12 of 12 persons (100%) 8 to 43 days after they had had a breakthrough infection.Prevaccinated, noninfected persons served as controls to determine the baseline antibody level (Fig. 1A, and the Methods section and Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).The level of salivary anti-RBD IgA antibodies showed a stronger correlation with the level of RBD-specific secretory immunoglobulin (sIg, detected with the use of an antisecretory component antibody) (r = 0.62, P<0.001) than with RBD-specific serum IgA antibodies (r = 0.35, P = 0.001), findings that suggest that most of the measured salivary IgA was secretory IgA (sIgA) that was produced locally in the salivary glands.Furthermore, salivary anti-RBD IgM antibodies were detected in only a low percentage of vaccinated persons (10%), which suggests that the majority of measured sIg antibodies were RBD-specific sIgA antibodies.The salivary RBD-specific IgA antibodies were maintained at a low level for more than 5 months after the second and third dose of vaccine.After breakthrough infection during the omicron BA.1 wave, salivary-specific IgA antibodies were induced and sustained at a higher level (Fig. 1B).Among 29 vaccinated persons monitored for 6 months after the second dose of vaccine, salivary anti-RBD IgA and sIg levels, but not plasma anti-RBD IgG levels or salivary anti-RBD IgG or IgM levels, were significantly lower in 9 persons with breakthrough infection than in 20 persons without such infection (P = 0.002 for salivary
Tom Nolan’s research reviews—24 November 2022
Authors: Tom Nolan
Journal: BMJ (2022)

New hope for lipid profile chatLooking for something new to spice up those cholesterol consultations?Lipoprotein(a) might be just what you're looking for.It's thought to be a marker of cardiovascular disease and therefore a candidate for new preventive treatments.A phase 2, dose-finding trial examined the effect of olpasiran (which reduces lipoprotein(a) synthesis in the liver) on lipoprotein(a) levels.This small study, which recruited 281 people with established atherosclerotic cardiovascular disease and high lipoprotein(a) levels, did indeed find a dose dependent reduction in lipoprotein(a) levels in those who received olpasiran.But it's early days: will this reduction translate into clinically meaningful endpoints?Until then, it's back to the familiar "good and bad cholesterol" and "let's take a look at your overall risk" chat.
Nivolumab serum concentration in metastatic melanoma patients could be related to outcome and enhanced immune activity: a gene profiling retrospective analysis
Authors: Domenico Mallardo, Diana Giannarelli, Maria Grazia Vitale, Domenico Galati, Giusy Trillò, Assunta Esposito, Maria Antonietta Isgrò, Grazia D'Angelo, Lucia Festino, Vito Vanella, Claudia Trojaniello, Andrew White, Teresa De Cristofaro, Michael Bailey, Sandro Pignata, Corrado Caracò, Antonella Petrillo, Paolo Muto, Piera Maiolino, Alfredo Budillon, Sarah Warren, Ernesta Cavalcanti, Paolo Antonio Ascierto
Journal: Journal for ImmunoTherapy of Cancer (2022)

Nivolumab is an anti-PD-1 antibody approved for treating metastatic melanoma (MM), for which still limited evidence is available on the correlation between drug exposure and patient outcomes.In this observational retrospective study, we assessed whether nivolumab concentration is associated with treatment response in 88 patients with MM and if the patient's genetic profile plays a role in this association.We observed a statistically significant correlation between nivolumab serum concentration and clinical outcomes, measured as overall and progression-free survival. Moreover, patients who achieved a clinical or partial response tended to have higher levels of nivolumab than those who reached stable disease or had disease progression. However, the difference was not statistically significant. In particular, patients who reached a clinical response had a significantly higher concentration of nivolumab and presented a distinct genetic signature, with more marked activation of ICOS and other genes involved in effector T-cells mediated proinflammatory pathways.In conclusion, these preliminary results show that in patients with MM, nivolumab concentration correlates with clinical outcomes and is associated with an increased expression of ICOS and other genes involved in the activation of T effectors cells.
Contextual inference in learning and memory
Authors: James B. Heald, Máté Lengyel, Daniel M. Wolpert
Journal: Trends in Cognitive Sciences (2022)

Context is widely regarded as a major determinant of learning and memory across numerous domains, including classical and instrumental conditioning, episodic memory, economic decision-making, and motor learning. However, studies across these domains remain disconnected due to the lack of a unifying framework formalizing the concept of context and its role in learning. Here, we develop a unified vernacular allowing direct comparisons between different domains of contextual learning. This leads to a Bayesian model positing that context is unobserved and needs to be inferred. Contextual inference then controls the creation, expression, and updating of memories. This theoretical approach reveals two distinct components that underlie adaptation, proper and apparent learning, respectively referring to the creation and updating of memories versus time-varying adjustments in their expression. We review a number of extensions of the basic Bayesian model that allow it to account for increasingly complex forms of contextual learning.
Impact of COVID-19 on the physical activity, quality of life and mental health of adolescent athletes: a 2-year evaluation of over 17 000 athletes
Authors: Andrew Watson, Kristin Haraldsdottir, Kevin Biese, Allison Schwarz, Scott Hetzel, Claudia Reardon, M Alison Brooks, David R Bell, Timothy McGuine
Journal: British Journal of Sports Medicine (2022)

To evaluate the changes in mental health, quality of life (QOL) and physical activity (PA) among adolescent athletes during the COVID-19 pandemic as organised sports resumed.Adolescent athletes completed surveys including demographic and sport participation information, 7-item Generalized Anxiety Disorder, 9-item Patient Health Questionnaire, Pediatric Quality of Life Inventory and the Hospital for Special Surgery Pediatric Functional Activity Brief Scale in May 2020 following COVID-19-related sport cancellations (Spring20) and after returning to sports in May 2021 (Spring21). The groups were balanced by inverse propensity score weighting and compared using analysis of variance models and ordinal regression models.17 421 participants were included (Spring20=13 002; Spring21=4419; 16.2±1.2 years; 53% female). Anxiety was significantly lower (better) in Spring21 (Spring20=7.0, 95% CI 6.9 to 7.1; Spring21=4.9, 95% CI 4.8 to 5.0, p<0.001), as was the prevalence of moderate to severe anxiety (Spring20=29.4%, Spring21=17.1%, p<0.001). Depression was significantly improved in Spring21 (Spring20=7.6, 95% CI 7.5 to 7.7; Spring21=4.6, 95% CI 4.5 to 4.8, p<0.001), as was the prevalence of moderate to severe depression (Spring20=32.2%, Spring21=15.4%, p<0.001). Athletes in Spring21 reported higher QOL (Spring20=79.6, 95% CI 79.3 to 79.9; Spring21=84.7, 95% CI 84.4 to 85.0, p<0.001) and increased levels of PA (Spring20=13.8, 95% CI 13.6 to 13.9; Spring21=22.7, 95% CI 22.6 to 22.9, p<0.001).Early COVID-19 sports restrictions were associated with worsening mental health in adolescents. In 2021, after returning to sports, athletes reported significant improvements in mental health, QOL and PA, although mental health adversities remain an important priority.
Mortality in non-exacerbating COPD: a longitudinal analysis of UK primary care data
Authors: Alexandra Lenoir, Hannah Whittaker, Alicia Gayle, Debbie Jarvis, Jennifer K Quint
Journal: Thorax (2022)

Introduction Non-exacerbating patients with chronic obstructive pulmonary disease (COPD) are a less studied phenotype. We investigated clinical characteristics, mortality rates and causes of death among non-exacerbating compared with exacerbating patients with COPD. Methods We used data from the Clinical Practice Research Datalink, Hospital Episode Statistics and Office for National Statistics between 1 January 2004 and 31 December 2018. Ever smokers with a COPD diagnosis with minimum 3 years of baseline information were included. We compared overall using Cox regression and cause-specific mortality rates using competing risk analysis, adjusted for age, sex, deprivation, smoking status, body mass index, GOLD stage and comorbidities. Causes of death were identified using International Classification of Diseases-10 codes. Results Among 67 516 patients, 17.3% did not exacerbate during the 3-year baseline period. Mean follow-up was 4 years. Non-exacerbators were more likely to be male (63.3% vs 52.4%, p&lt;0.001) and less often had a history of asthma (33.9% vs 43.6%, p&lt;0.001) or FEV 1 &lt;50% predicted (23.7 vs 31.8%) compared with exacerbators. Adjusted HR for overall mortality in non-exacerbators compared with exacerbators was 0.62 (95% CI 0.56 to 0.70) in the first year of follow-up and 0.87 (95% CI 0.83 to 0.91) thereafter. Non-exacerbating patients with COPD died less of respiratory causes than exacerbators (29.2% vs 40.3%) and more of malignancies (29.4% vs 23.4%) and cardiovascular diseases (26.2% vs 22.9%). HRs for malignant and circulatory causes of death were increased after the first year of follow-up. Discussion In this primary care cohort, non-exacerbators showed distinct clinical characteristics and lower mortality rates. Non-exacerbators were equally likely to die of respiratory, malignant or cardiovascular diseases.
Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex
Authors: Shuang Liu, Hyejung Won, Declan Clarke, Nana Matoba, Saniya Khullar, Yudi Mu, Daifeng Wang, Mark Gerstein
Journal: Genome Medicine (2022)

Abstract Background Neuropsychiatric disorders afflict a large portion of the global population and constitute a significant source of disability worldwide. Although Genome-wide Association Studies (GWAS) have identified many disorder-associated variants, the underlying regulatory mechanisms linking them to disorders remain elusive, especially those involving distant genomic elements. Expression quantitative trait loci (eQTLs) constitute a powerful means of providing this missing link. However, most eQTL studies in human brains have focused exclusively on cis-eQTLs, which link variants to nearby genes (i.e., those within 1 Mb of a variant). A complete understanding of disease etiology requires a clearer understanding of trans-regulatory mechanisms, which, in turn, entails a detailed analysis of the relationships between variants and expression changes in distant genes. Methods By leveraging large datasets from the PsychENCODE consortium, we conducted a genome-wide survey of trans-eQTLs in the human dorsolateral prefrontal cortex. We also performed colocalization and mediation analyses to identify mediators in trans-regulation and use trans-eQTLs to link GWAS loci to schizophrenia risk genes. Results We identified ~80,000 candidate trans-eQTLs (at FDR&lt;0.25) that influence the expression of ~10K target genes (i.e., “trans-eGenes”). We found that many variants associated with these candidate trans-eQTLs overlap with known cis-eQTLs. Moreover, for &gt;60% of these variants (by colocalization), the cis-eQTL’s target gene acts as a mediator for the trans-eQTL SNP's effect on the trans-eGene, highlighting examples of cis-mediation as essential for trans-regulation. Furthermore, many of these colocalized variants fall into a discernable pattern wherein cis-eQTL’s target is a transcription factor or RNA-binding protein, which, in turn, targets the gene associated with the candidate trans-eQTL. Finally, we show that trans-regulatory mechanisms provide valuable insights into psychiatric disorders: beyond what had been possible using only cis-eQTLs, we link an additional 23 GWAS loci and 90 risk genes (using colocalization between candidate trans-eQTLs and schizophrenia GWAS loci). Conclusions We demonstrate that the transcriptional architecture of the human brain is orchestrated by both cis- and trans-regulatory variants and found that trans-eQTLs provide insights into brain-disease biology.
Deep immune profiling uncovers novel associations with clinical phenotypes of multisystem inflammatory syndrome in children (MIS-C)
Authors: Christopher John Redmond, Moses M Kitakule, Aran Son, McKella Sylvester, Keith Sacco, Ottavia Delmonte, Francesco Licciardi, Riccardo Castagnoli, M Cecilia Poli, Yasmin Espinoza, Camila Astudillo, Sarah E Weber, Gina A Montealegre Sanchez, Karyl S Barron, Mary Magliocco, Kerry Dobbs, Yu Zhang, Helen Matthews, Cihan Oguz, Helen C Su, Luigi D Notarangelo, Pamela Frischmeyer-Guerrerio, Daniella M Schwartz
Journal: Annals of the Rheumatic Diseases (2022)